U.S. patent application number 10/222930 was filed with the patent office on 2004-02-19 for sustained release pharmaceutical composition of a cephalosporin antibiotic.
This patent application is currently assigned to Orchid Health Care. Invention is credited to Boldhane, Sanjay Parbhatrao, Jindal, Kour Chand, Kshirsagar, Rajesh Suresh.
Application Number | 20040033262 10/222930 |
Document ID | / |
Family ID | 31715086 |
Filed Date | 2004-02-19 |
United States Patent
Application |
20040033262 |
Kind Code |
A1 |
Kshirsagar, Rajesh Suresh ;
et al. |
February 19, 2004 |
Sustained release pharmaceutical composition of a cephalosporin
antibiotic
Abstract
This invention relates to a sustained release pharmaceutical
composition comprising at least a cephalosporin antibiotic, a
mixture of polymers and other pharmaceutically acceptable
excipients; in the composition, polymers are selected from mixture
of galactomannans and neutral swellable polymers, which releases
the active ingredient in a predetermined manner.
Inventors: |
Kshirsagar, Rajesh Suresh;
(Chennai, IN) ; Boldhane, Sanjay Parbhatrao;
(Chennai, IN) ; Jindal, Kour Chand; (Chennai,
IN) |
Correspondence
Address: |
OLIFF & BERRIDGE, PLC
P.O. BOX 19928
ALEXANDRIA
VA
22320
US
|
Assignee: |
Orchid Health Care
Chennai
IN
|
Family ID: |
31715086 |
Appl. No.: |
10/222930 |
Filed: |
August 19, 2002 |
Current U.S.
Class: |
424/468 ;
514/200; 514/54 |
Current CPC
Class: |
A61K 9/2027 20130101;
A61K 47/36 20130101; A61K 31/546 20130101; A61K 9/205 20130101;
A61K 31/736 20130101; A61K 47/32 20130101; A61K 9/2018 20130101;
A61K 9/2054 20130101; A61K 9/204 20130101; A61K 31/545
20130101 |
Class at
Publication: |
424/468 ; 514/54;
514/200 |
International
Class: |
A61K 031/545; A61K
031/736; A61K 009/20; A61K 009/22 |
Claims
1. A sustained release pharmaceutical composition comprising at
least a cephalosporin antibiotic, a mixture of galactomannans and
neutral swellable polymers and other pharmaceutically acceptable
excipients.
2. The composition according to claim 1, which comprises about 30%
to about 90% by weight of a cephalosporin antibiotic; about 2% to
about 30% by weight of said mixture of polymers selected from about
0.1% to about 15% by weight galactomannans and about 0.1% to about
15% of neutral swellable polymer by weight of sustained release
composition.
3. The composition according to claim 1, which comprises about 30%
to about 90% by weight of cephalosporin antibiotic, about 2% to
about 20% by weight of mixture of said polymers selected from
galactomannans in an amount from about 0.1% to about 12% by weight
and neutral swellable polymer in an amount from about 0.1% to about
12% by weight of sustained release composition.
4. The composition as claimed in claim 1, is in the form of a
tablet.
5. The composition as claimed in claim 1, wherein the cephalosporin
antibiotic is released at a rate suitable for once daily or twice
daily administration.
6. The composition according to claim 1, wherein the cephalosporin
antibiotic is selected from Cephalexin, Cefprozil, Cefditoren
pivoxil, Cefadroxil, Cefpodoxime proxetil, Cefuroxime axetil,
Cefaclor, Cefamandole, Cefoxitin, Cephalothin, Cephaprin,
Ceftizoxime, Cefonicid and their pharmaceutically acceptable
hydrates, salts or esters.
7. The composition according to claim 1, wherein the galactomannans
used is selected from the group consisting of xanthan gum, guar gum
or locuat bean gum.
8. The composition according to claim 1, wherein the excipients
used are water soluble or water dispersible diluents, binders or
lubricant.
9. The composition according to claim 8, wherein the water soluble
or water dispersible diluent consisting of about 1 to 30% by weight
of the composition.
10. The composition as claimed in claim 8, wherein the water
soluble diluents used are lactose, mannitol, glucose, sorbitol,
maltose, dextrates or dextrins.
11. The composition as claimed in claim 8, wherein the water
dispersible diluents used is microcrystalline cellulose or
pregelatinized starch.
12. The composition as claimed in claim 8, wherein the tablet
binder concentration is in the range of about 0.2% to about 12% by
weight either alone or in combination of the total weight of
composition.
13. The composition as claimed in claim 8, wherein the binder is
selected from polyvinyl pyrrolidone, hydroxypropyl methylcellulose,
hydroxypropyl cellulose, gelatin, pregelatinized starch, sugar and
like.
14. The composition as claimed in claim 8, wherein the lubricant
concentration is in the range of about 0.2% to about 5% by weight
either alone or in combination of the total weight of
composition.
15. The composition as claimed in claim 8, wherein the lubricant
used is selected from talc, stearic acid, magnesium stearate,
colloidal silicon dioxide, calcium stearate, zinc stearate or
hydrogenated vegetable oil.
16. A process for the preparation of the sustained release
pharmaceutical composition, the said method comprising steps of: i)
mixing an active ingredient, pharmaceutically acceptable excipients
and galactomannans in a mixer, ii) granulating the mixture of step
(i) with a neutral swellable polymer, iii) drying the granules of
step (ii) by either tray drying or fluid bed drier, iv) milling the
dried granules of step (iii) followed by addition of dry binder and
a lubricant, and v) compressing the lubricated milled granules of
step (iv) into tablets using a tablet press and if desired coating
the tablets with pharmaceutically acceptable agents.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a sustained release pharmaceutical
composition comprising at least a cephalosporin antibiotic, a
mixture of polymers and other pharmaceutically acceptable
excipients. The polymers are selected from mixture of
galactomannans and neutral swellable polymers which releases the
active ingredient in a predetermined manner, the said
galactomannans being selected from the group consisting of xanthan
gum and neutral swellable polymer selected from the group
consisting of poly (ethyl acrylate: methyl methacrylate) 2:1.
BACKGROUND OF THE INVENTION
[0002] While many compounds are known to be useful as
pharmacologically active substances, some of them have relatively
short biological half life and needs to be administered several
times a day in order to achieve desired therapeutic effects.
Especially, the drugs used in treatment of microbial infections are
required to be given more than once during a dosage regimen.
[0003] In an anti-microbial therapy, the main requirement is to
maximize the blood concentration, preferably several folds higher
than the minimum inhibitory concentration (MIC) for the active
agent, yet to minimize both the risks of toxicity to the patient
and of promoting microbial resistance. Although, oral
administration will be the preferred route, in the case of
antibiotics this route is frequently unattractive because of their
low or variable oral bioavailability. In addition, extremely high
plasma concentrations of antibiotics are frequently required to
achieve the MIC values towards certain gram-negative bacteria
(antibiotics and chemotherapy; anti-infective agents and their use
in therapy 7.sup.th edition Ed. By O'grady F, Finch R G, Lambert H
P; Greenwood D; Churchill Livingstone 1997).
[0004] Sustained release preparation of drugs are advantageous as
the administration frequency can be reduced by maintaining a
constant plasma concentration of drug over an extended period of
time to ensure sustained effect of active ingredient well above the
MIC levels. In addition, these preparations are also expected to
decrease side effects by suppressing the rapid rise in the blood
levels of the drug.
[0005] This has been primarily achieved by development of a novel
drug delivery system utilizing diverse techniques and principles.
Amongst these, known in the art is one such delivery system, which
employs hydrophilic polymers to sustained or modified release
pharmaceutical composition. In the modified release solid dosage
forms comprising a drug, such drug is dispersed uniformly in a
mixture of polymers and the release of the drug is controlled
primarily by diffusion of the drug, or by surface erosion of the
hydrophilic polymers into the surrounding medium or by a
combination of both processes. Control of the rate of release can
produce constant blood levels of the active ingredient that may
result in reducing the frequency of administration, thereby
improving patient compliance to the dosage regimen.
[0006] The relevant prior art methods, which teach adaptation of
diverse delivery system for the sustained release of the active
ingredient, are as follows:
[0007] U.S. Pat. No. 6,120,803 discloses an active agent dosage
form, which is adapted for retention in the stomach and useful for
the prolonged delivery of an active agent to a fluid environment.
The active agent dosage form is a polymer composition that swells
upon contact with the fluid of the stomach. A portion of the
polymer composition is surrounded by a band of insoluble material
that prevents the covered portion of the polymer composition from
swelling and provides a segment of the dosage form that is of
sufficient rigidity to withstand the contraction of the stomach and
delay expulsion of the dosage form from the stomach until
substantially all the active agent has been dispensed.
[0008] U.S. Pat. No. 5,128,142 discloses a controlled release
formulation comprising an absorbate of a mixture of
pharmaceutically active ingredients and an inactive substance
absorbed on a cross linked polymer. The inactive substance is
selected to modify the dissolution of active ingredients from the
cross linked polymer in vivo. The inactive substance is preferably
present in the absorbate in an amount of 0.5-3 parts by weight
relative to 1 part by weight of the active ingredients.
[0009] U.S. Pat. No. 4,968,508 discloses a sustained release matrix
tablet comprising from about 0.1% to about 90% by weight of
Cefaclor, about 5% of about 29% by weight by hydrophilic polymer
and about 0.5% to about 25% by weight of an acrylic polymer which
dissolve at a pH in the range of about 5.0 to about 7.4, the total
weight of polymers being less than 30% by weight of the
formulation. Although a specific Cefaclor formulation is claimed
the text suggests that the matrix formulation is suitable for
weakly basic drugs and particularly suitable for Cephalexin and
Cefaclor.
[0010] International Publication number WO 02/41876 discloses a
pharmaceutical composition in the form of a tablet for controlled
release of an active ingredient comprising a cephalosporin
antibiotic such as Cephalexin, Cefaclor or their pharmaceutically
acceptable hydrates, salts or esters as active ingredients, and a
mixture of hydrophilic polymers selected from the group consisting
of at least one sodium alginate and at least one xanthan gum as
controlled release matrix and optionally probenecid as an
antibiotic adjuvant as either immediate release or controlled
release part. The composition may contain one or more of a
water-soluble and/or water dispersible diluent. The quantity of the
hydrophilic polymers matrix still provides the desired once a day
profile.
[0011] International Publication number WO 02/36126 discloses a
fast disintegrating controlled release oral composition comprising
a core material containing Cefuroxime Axetil present as controlled
release form, the Cefuroxime axetil-being provided with an outer
coating of a copolymer selected from aqueous dispersions of enteric
methacrylic acid and methacrylic acid esters anionic copolymers
having carboxyl group as the functional group or mixture thereof
and an inner coating of a sustained release copolymer selected from
aqueous dispersions of acrylate or methacrylate pH independent
copolymers having quaternary ammonium group as a functional group
or mixture thereof. Additionally the coating composition may
contain plasticizers. The composition is suitable for once daily
administration.
[0012] U.S. Pat. No. 4,250,166 discloses a long acting Cephalexin
preparation comprising of normal quick releasing Cephalexin and
particulate Cephalexin coated with a copolymer of methacrylates and
methacrylic acid which dissolves at pH from 5.5 to 6.5 and the
potency ratio of the normal Cephalexin to coated Cephalexin is
between 40:60 and 25:75.
[0013] U.S. Pat. No. 6,399,086 discloses a controlled release
cephalosporin antibiotic agent preferably amoxicillin trihydrate in
a hydrophilic and/or hydrophobic polymer matrix such that at least
50% but not more than 67.61.+-.5.78% of the active agent is
released within 3 to 4 hrs from oral administration and remainder
is released at a controlled rate from the said composition. The
composition teaches the use of commonly used hydrophilic polymers
such as hydrophilic cellulose derivatives, hydrophilic methacrylic
acid derivatives, chitosan, and alginates. Preferably, use of
hydrophilic cellulose derivative such as methylcellulose,
hydroxypropyl methycellulose, hydroxyethyl cellulose is cited.
[0014] The hydrophobic polymers used in the invention are
acrylamides and polyamido derivatives and hydrophobic methacrylic
acid derivatives. The preferred hydrophobic polymer is ethyl
cellulose.
[0015] However with this profile wherein 67.61.+-.5.78% of the drug
is already out of the matrix, and considering a very short
half-life of most cephalosporins such as Cephalexin and Cefprozil
(55 min and 70 min) respectively the drug profile achieved cannot
be suitable for once daily administration. Hence, it is necessary
that the matrix formulation should release the drug over extended
period of time.
[0016] The corresponding International Publication number WO
98/22091 discloses a controlled release oral drug delivery system
comprising as active ingredient a betalactam antibiotic having a
specific absorption site in a small intestine in a hydrophilic
and/or hydrophobic polymer matrix such that at least 50% of the
active agent is released within 3 to 4 hrs from oral administration
and remainder is released at a controlled rate from the said
composition.
[0017] U.S. Pat. No. 6,083,532 discloses a sustained release tablet
comprising a drug to be released at a controlled rate and a
sustained release formulation comprising atleast three different
type of polymers including a pH dependent gelling polymer, a pH
independent gelling polymer and an enteric polymer. The pH
dependent gelling polymer comprises at least one of an alginate, a
carboxyvinyl polymer, or a salt of carboxymethyl cellulose. The pH
independent gelling polymer comprises at least one of a HPMC, HPEC,
a HPC, a HEC, a methylcellulose, a xanthan gum or a polyethylene
oxide. The enteric polymer comprises at least one of a polyacrylate
material, a cellulose acetate phthalate, cellulose phthalate
hydroxy propyl methyl ether, a polyvinyl acetate phthalate, a
hydroxy propyl methyl cellulose acetate succinate, a cellulose
acetate trimelliatate or shellac.
[0018] U.S. Pat. No. 5,948,440 discloses a controlled release
tablet of an active ingredient comprising of Cefaclor, Cephalexin
or their pharmaceutically acceptable hydrates, salts or esters as
active ingredients and a mixture of hydrophilic polymers selected
from the group consisting of at least one hydroxy propyl
methylcellulose and at least one hydroxyl propyl cellulose. The
composition optionally also contains one or more of a water soluble
or water dispersible diluent, the quantities are such that the
therapeutically effective active ingredient is released at a rate
for twice daily administration of the pharmaceutical
composition.
[0019] Japanese Patent JP 57165392A discloses a long acting
Cephalexin tablet comprising Cephalexin mixed with .gtoreq.10% w/w
oils and fats (e.g. higher fatty acid, higher alcohol, alcohol
ester etc) and with a vehicle such as magnesium stearate and the
mixture is pressed, formed into granules passing through a 20 mesh
sieve, and subjected to the slug formed process to obtain a high
quality long acting tablets. The rate of dissolution of Cephalexin
can be controlled by selecting the kind of oils and fats and the
number of the time of slug formation process.
[0020] International Publication number WO 00/15198 teaches
controlled delivery pharmaceutical composition having temporal and
spatial control, comprising a drug, a gas generating component a
swelling agent, a viscolyzing agent and optionally a gel forming
polymer. The viscolyzing agent initially and the gel forming
polymer thereafter form a hydrated gel matrix which entraps the
gas, causing the tablet to float so that it is retained in the
stomach thereby providing spatial control and at the same time
resulting in sustained release of the drug providing temporal
control.
[0021] The combination of gas generating component, swelling agent
and viscolyzing agent results in the controlled drug delivery
systems. Thus all these components are essential for achieving the
temporal and spatial control. A preferred once daily Ciprofloxacin
formulation comprising 69.9% Ciprofloxacin base, 0.34% sodium
alginate, 1.03% xanthan gum, 13.7% sodium bicarbonate, 12.1% cross
linked polyvinyl pyrrolidone and optionally other excipients is
disclosed.
[0022] Sustained release preparation of drugs are advantageous in
the administration, frequency can be reduced by maintaining a
constant plasma concentration of drug over an extended period of
time to ensure sustained effect of active ingredient.
[0023] Since the antibiotics are high frequency/high dosing,
extended release drug delivery systems have not been very
successful in reducing the frequency. The present invention is
based on the observation that the release of active ingredient from
the delivery system is controlled by the specific polymers present
in the matrix and in specific concentrations, thus allowing blood
levels above MIC over extended period of time such that the
frequency of the dosage form can be reduced to twice daily or once
daily.
OBJECTIVES OF THE INVENTION
[0024] The main object of the present invention is to provide a
sustained release of the active ingredient from the pharmaceutical
composition, which has blood levels above MIC over extended period
of time.
[0025] Another objective of the present invention is to provide a
sustained release pharmaceutical composition suitable for twice
daily or once daily dosage form.
[0026] Yet another objective of the present invention is to provide
a sustained release pharmaceutical composition, which releases the
active ingredient in a predetermined manner.
[0027] Yet another objective of the present invention is to provide
sustained release pharmaceutical composition of a cephalosporin
antibiotic.
SUMMARY OF THE INVENTION
[0028] Accordingly, the present invention relates to a sustained
release pharmaceutical composition comprising at least a
cephalosporin antibiotic, a mixture of galactomannans and neutral
swellable polymers and other pharmaceutically acceptable
excipients.
[0029] The polymers are selected in such a way to give sustained
release of the active ingredient in a predetermined manner.
[0030] Preferably, the invention relates to sustained release
pharmaceutical composition comprising a cephalosporin antibiotic, a
mixture of galactomannans and neutral swellable polymers, said
galactomannans being selected from the group consisting of xanthan
gum and neutral swellable polymer selected from the group
consisting of poly (ethyl acrylate: methyl methacrylate) 2:1.
[0031] More preferably, the present invention relates to the
sustained release pharmaceutical composition which comprises about
30% to about 90% by weight of a cephalosporin antibiotic; about 2%
to about 30% by weight of said mixture of polymers being selected
from group consisting of about 0.1% to about 15% by weight of
galactomannans, about 0.1% to about 15% of neutral swellable
polymer by weight of sustained release composition.
[0032] Still more preferably, the present invention relates to the
sustained release pharmaceutical composition comprises about 30% to
about 90% by weight of cephalosporin antibiotic, about 2% to about
20% by weight of mixture of said polymers being selected from group
consisting of galactomannans in an amount from about 0.1% to about
12% by weight and neutral swellable polymer in an amount from about
0.1% to about 12% by weight of sustained release composition.
[0033] According to yet another embodiment of the present
invention, the sustained release pharmaceutical composition may be
prepared by wet granulation method, the said method comprising
steps of:
[0034] i. mixing an active ingredient, pharmaceutically acceptable
excipients and galactomannans in a mixer,
[0035] ii. granulating the mixture of step (i) with a neutral
swellable polymer,
[0036] iii. drying the granules of step (ii) by either tray drying
or fluid bed drier,
[0037] iv. milling the dried granules of step (iii) followed by
addition of a dry binder and a lubricant,
[0038] v. compressing the lubricated milled granules of step (iv)
into tablets using a tablet press and if desired coating the
tablets.
[0039] A binder such as low viscosity hydroxypropyl methyl
cellulose (HPMC) can be added optionally, during wet
granulation.
DETAILED DESCRIPTION OF THE INVENTION
[0040] In an embodiment of the present invention, cephalosporin
antibiotic used as active ingredient include Cephalexin, Cefprozil,
Cefditoren pivoxil, Cefadroxil, Cefpodoxime proxetil, Cefuroxime
axetil, Cefaclor, Cefamandole, Cefoxitin, Cephalothin, Cephaprin,
Ceftizoxime, Cefonicid and their pharmaceutically acceptable
hydrates, salts or esters.
[0041] In another embodiment of the present invention,
cephalosporin antibiotic may be present in an amount from about 30
to about 90% by weight of the sustained release composition.
Further, the cephalosporin antibiotic may be present in the amount
from 100 mg to 2000 mg per dosage.
[0042] In an embodiment of the present invention, the
galactomannans used is selected from the group consisting of
xanthan gum, guar gum, locuat bean gum and the like. In an
embodiment of the present invention, the neutral swellable polymer
used is Poly (ethyl acrylate: methyl methacrylate) 2:1.
[0043] The composition optionally comprises of one or more
excipients such as water soluble or water dispersible diluents,
binders, lubricant wherein the quantities of galactomannans and
neutral swellable polymers, and water soluble/water dispersible
diluents are such that the therapeutically effective active
ingredients is released at a rate suitable for once or twice daily
administration of the dosage form.
[0044] The composition may contain one or more pharmaceutically
acceptable diluent in amount about 1% to about 30% by weight of the
total weight of composition.
[0045] These diluents may be water soluble or water dispersible.
Examples of water soluble diluents that may be used in the present
invention include lactose, mannitol, glucose, sorbitol, maltose,
dextrates, dextrins and the like. Water dispersible diluents that
may be used such as microcrystalline cellulose, pregelatinized
starch, and the like. In the preferred embodiment, the diluent is
lactose in amount from about 5% to about 20% by weight of the
sustained release composition.
[0046] The composition may also contain a tablet binder at a
concentration in the range of about 0.2% to about 12% by weight
either alone or in combination of the total weight of composition.
The binder that may be used includes polyvinyl pyrrolidone,
hydroxypropyl methylcellulose, hydroxypropyl cellulose, gelatin,
pregelatinized starch, sugar and the like.
[0047] The composition may also contain a tablet lubricant at a
concentration in the range of about 0.2% to about 5% by weight
either alone or in combination of the total weight of composition.
The lubricant that may be used include, talc, stearic acid,
magnesium stearate, colloidal silicon dioxide, calcium stearate,
zinc stearate, hydrogenated vegetable oil and the like.
[0048] Xanthan gum is a high molecular weight, anionic, natural
heteropolysaccharide gum produced by aerobic fermentation with the
organism xanthomonas campestris. It contains D-glucose, D-mannose,
D-glucuronate in the molar ratio of 2.8:2.0:20 and is partially
acetylated with about 4.7% acetyl. Xanthan gum also includes about
3.0% pyruvate, which is attached to a single unit D-glucopyromosyl
side chain as a metal. It dissolves in hot or cold water and the
viscosity of aqueous solutions of xanthan gum is only slightly
affected by changes in the pH of solution between 1 and 11.
[0049] Xanthan gum has a branched or helical configuration, thus
results in excellent water wicking properties. When xanthan gum
comes into contact with an aqueous medium of gastrointestinal
tract, it hydrates and swells to form a gel. It has good swelling
action on contact with an aqueous medium and overcomes the problem
encountered by other gums, which either do not hydrate rapidly
enough or hydrate too rapidly. Xanthan gum alone when used as a
matrix forming agent in sustained release tablets, releases the
drug slightly faster in acidic media, due to more rapid initial
surface erosion than at higher pH. After hydration of the gum the
drug release is essentially pH independent.
[0050] During the course of our studies, we found that when xanthan
gum alone was used as matrix forming agent, the initial release of
the cephalosporins was rapid, but the release retarded at later
stage due to hydration of xanthan gum to forming a gel. The
following tables disclose a typical composition and percent
cephalexin released over a period of time.
1 Ingredients Weight (mg/tablet) % w/w Cephalexin 795.32 75.74
Lactose 139.18 13.26 Xanthan gum 105.0 10.0 Magnesium stearate 10.5
1.0
[0051]
2 Time (hour) Percent Cephalexin Released 1 40.0 2 45.3 3 50.2 4
56.4 5 60.2 6 62.1
[0052] Xanthan gum polymers that may be used in the present
invention include Xantural.TM. (Kelco), Rhodigel.TM. available from
(Rhodia, USA) and xanthan gum (Jungbunzlauer, Austria.)
[0053] Poly (ethyl acrylate: methyl methacrylate) 2:1 is latex
available only in aqueous dispersion either 30% or 40% solids
including neutral emulsifier. It has no functional group and is
practically neutral. Therefore, the films formed are insoluble in
water or in aqueous medium over the entire pH range. The polymer
swells in aqueous media and gives permeable membrane. The
permeability is independent of pH.
[0054] We also found that when poly (ethyl acrylate: methyl
methacrylate) 2:1 was used alone the release was retarded, however
the tablet integrity was lost after 2 hours.
3 Ingredients Weight (mg/tablet) % w/w Cephalexin 795.32 75.74
Lactose 139.18 13.26 Eudragit NE 30D 105.0 10.0 Magnesium stearate
10.5 1.0
[0055]
4 Time (hour) Percent Cephalexin Released 1 18.9 2 61.76 3 98.6
(Integrity lost)
[0056] Poly (ethyl acrylate: methyl methacrylate) 2:1 is available
under the brand name of Eudragit NE 30D from Rohm Pharma Company,
Germany.
[0057] According to the present invention, when a pH independent
neutral swellable polymer was mixed with xanthan gum along with
active ingredient, the release from the composition was controlled
initially and uniformly released over a period of time such that
desired blood levels were achieved suitable for twice or once daily
dosage form.
[0058] The combination of xanthan gum and poly (ethyl acrylate:
methyl methacrylate) 2:1 is a unique combination suitable for
sustained release of active ingredients, which are to be
administered for once daily administration. Both the polymers give
a pH independent release profile.
[0059] The granulation of the blend of active ingredient, diluent,
binder, lubricant and xanthan gum with poly (ethyl acrylate: methyl
methacrylate) 2:1 aqueous dispersions, form thinner but more
effective film layers, where drug particles and granulating
excipients are partially impregnated and during compression they
are embedded in a fine network of thin polymer layers. When the
tablet comes in contact with aqueous media of the gastrointestinal
tract the thin film of poly (ethyl acrylate: methyl methacrylate)
2:1 controls the penetration of digestive fluids in to the
composition and thus avoids initial erosion of xanthan gum, which
is high at acidic pH. The poly (ethyl acrylate: methyl
methacrylate) 2:1 slowly hydrates without disrupting the
hydrophilic composition formed by the heteropolysaccharide. The
insoluble poly (ethyl acrylate: methyl methacrylate) 2:1 forms a
sponge like structure, which behaves as inert matrices. Once the
xanthan gum is completely hydrated, it forms a gel and then, the
release of active ingredient is governed by diffusion of dissolved
drug through the pores, channels and capillaries of the insoluble
polymer composition.
[0060] In the present invention, it was observed when these two
polymers were mixed together in appropriate concentration to form a
tablet, the release was controlled in such a manner that the dosage
form is suitable for once daily administration.
[0061] We have found surprisingly when we control the release of
the active ingredients so as to achieve a 14-16 hours release
profile, we were able to achieve the blood levels suitable for once
or twice daily dosage form.
[0062] The present invention is illustrated by the following
examples, are not intended to be limited to the scope of the
invention.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWING
[0063] FIG. 1 represents graphical representation of Comparative
plasma profile of Cephalexin OD v/s Cephalexin capsules
EXAMPLES
General Procedure for the Preparation of Sustained Release
Tablet
[0064] Cephalosporin antibiotic, galactomannans, lactose were
screened through 30 mesh sieve and granulated by aqueous
dispersions of Eudragit NE 30D. Granules were dried in either tray
drier or fluidized bed drier. The dried granules were milled,
followed by addition of dry binder such as low viscosity
hydroxypropyl methylcellulose and lubricant magnesium stearate.
Dissolution Method
[0065] For all the examples, the tablets were tested for Cephalexin
or Cefprozil in 900 ml of 0.1N HCl for 1 hour, after which the
dissolution media was changed to pH 6.8 phosphate buffer 900 ml.
The tablets were placed in 40-mesh basket (USP Type I) and rotated
at 100 rpm.
[0066] In the following examples, the composition and its
dissolution profiles are given in a tabular form.
Example 1
Composition
[0067]
5 Ingredients Weight (mg/tablet) % w/w Cephalexin 798.15 75.74
Lactose 188.15 18.26 Xanthan gum 21.0 2.0 Eudragit NE 30D 31.5 3.0
Magnesium stearate 10.5 1.0
Dissolution Profile
[0068]
6 Time (hour) Percent Cephalexin Released 1 19.25 2 26.44 4 44.0 6
59.57 8 70.4 10 78.5 12 81.9
Example 2
Composition
[0069]
7 Ingredients Weight (mg/tablet) % w/w Cephalexin 795.32 75.25
Lactose 107.68 10.26 Xanthan gum 31.5 3.0 Eudragit NE 30D 52.5 5.0
HPMC E5 52.5 5.0 Magnesium stearate 10.5 1.0
Dissolution Profile
[0070]
8 Time (hour) Percent Cephalexin Released 1 25.21 2 30.18 4 38.17 6
50.84 8 63.70 10 73.18 12 78.60 14 84.17
Example 3
Composition
[0071]
9 Ingredients Weight (mg/tablet) % w/w Cephalexin 795.32 75.24
Lactose 97.18 9.26 Xanthan gum 42.0 4.0 Eudragit NE 30D 52.5 5.0
HPMC E5 52.5 5.0 Magnesium stearate 10.5 1.0
Dissolution Profile
[0072]
10 Time (hour) Percent Cephalexin Released 1 22.42 2 30.25 4 41.62
6 48.33 8 54.54 10 60.70 12 66.30 14 71.80
Example 4
Composition
[0073]
11 Ingredients Weight (mg/tablet) % w/w Cephalexin 795.32 75.24
Lactose 86.68 8.26 Xanthan gum 52.5 5.0 Eudragit NE 30D 52.5 5.0
HPMC E5 52.5 5.0 Magnesium stearate 10.5 1.0
Dissolution Profile
[0074]
12 Time (hour) Percent Cephalexin Released 1 35.57 2 41.96 4 54.46
6 65.00
Example 5
Composition
[0075]
13 Ingredients Weight (mg/tablet) % w/w Cephalexin 795.32 75.24
Lactose 107.68 10.26 Xanthan gum 52.5 5.0 Eudragit NE 30D 42.0 4.0
HPMC E5 42.0 4.0 Magnesium stearate 10.5 1.0
Dissolution Profile
[0076]
14 Time (hour) Percent Cephalexin Released 1 26.3 2 31.5 4 39.8 6
47.7 8 51.2 10 56.1 12 62.9 14 69.87
Example 6
Composition
[0077]
15 Ingredients Weight (mg/tablet) % w/w Cephalexin 795.32 75.74
Lactose 107.68 9.26 Xanthan gum 42.0 4.0 Eudragit NE 30D 42.0 4.0
HPMC E5 52.5 5.0 Magnesium stearate 10.5 1.0
Dissolution Profile
[0078]
16 Time (hour) Percent Cephalexin Released 1 26.4 2 31.4 4 38.7 6
49.5 8 61.7 10 67.8 12 80.0 14 85.2
Example 7
Composition
[0079]
17 Ingredients Weight (mg/tablet) % w/w Cefprozil 1084.52 77.54
Lactose 118.48 8.46 Xanthan gum 56.0 4.0 Eudragit NE 30D 56.0 4.0
HPMC E5 70.0 5.0 Magnesium stearate 14.0 1.0
Dissolution Profile
[0080]
18 Time (hour) Percent Cefprozil Released 1 17.4 2 21.2 4 22.0 6
24.2 8 33.1 10 40.2 12 45.6 14 53.0
Example 8
Composition
[0081]
19 Ingredients Weight (mg/tablet) % w/w Cefprozil 1084.52 77.54
Lactose 90.48 8.46 Xanthan gum 42.0 3.0 Eudragit NE 30D 28.0 2.0
HPMC E5 140.0 10.0 Magnesium stearate 14.0 1.0
Dissolution Profile
[0082]
20 Time (hour) Percent Cefprozil Released 1 20.3 2 24.4 4 32.1 6
40.8 8 57.4 10 70.5 12 78.5 14 84.8
Bioavility Studies
[0083] The bioavility study was conducted for comparison between
conventional Cephalexin (500 mg) and sustained release composition
formulation of Cephalexin 2 tablets of 750 mg, prepared according
to the present invention. Eight healthy male volunteers were
selected for the study in which each volunteer was administered a
dose of the drug with 240 ml of water. The volunteers fasted
overnight and had a standard breakfast before taking the drug. The
desired blood levels upto 18 to 20 hours were achieved with the
composition prepared according to the present invention, clearly
indicating that in can used as once daily dosing. The data is
summarized in table below. FIG. 1 shows a plot of Comparative
plasma profile of Cephalexin OD v/s Cephalexin capsules.
21 Cephalexin OD Parameters Cephalexin Capsules 500 mg (750 mg
.times. 2 T) Cmax 13.45 20.01 (mcg/ml) Tmax (hrs) 2.18 4.87 AUC 0-t
mcg .multidot. h/ml 34.62 100.34
[0084] The cephalosporin antibiotic exhibits minimal concentration
dependent killing and produce short term or no persistent effect
with most bacteria. The killing rate of these antibiotics saturates
at concentrations of around 4 to 5 times the MBC, thus high
concentration will not kill the bacteria faster than lower
concentrations. It has also been suggested that a concentration
much greater than the MIC decreases in bacterial kill potency.
These findings have led to the hypothesis that continuously
maintained concentrations above a certain level, related to the MIC
would be more efficacious than the high peak through concentrations
obtained with an intermittent dosing regimen. From the
Pharmacokinetic data obtained, it is seen the sustained release
formulation has achieved the Time/MIC equivalent to 3 times the
dosing of conventional dosage regime which is essential for killing
the bacteria.
[0085] While there have been shown and described what are believed
to be the preferred embodiments of the present invention, it will
be apparent to those of ordinary skill in the pharmaceutical
formulating art that various modifications in the formulations and
processes herein described can be made without departing from the
scope of invention as it is defined by the appended claims.
* * * * *